Brain Delivery Systems via Mechanism Independent of Receptor-Mediated Endocytosis and Adsorptive-Mediated Endocytosis

Abstract

The endothelial cells of the brain form the blood-brain barrier (BBB) that denotes a major restraint for drug entry to the brain. Traditional attempts to bypass the BBB have been by formulation of drugs with lipophilicity or low molecular weight designed to enable transport via solute nutrient transporters. The identification of many new targets in the brain cells form new ways of thinking drug design as modern therapeutics could be proteins and molecules of genetic origins like siRNA and cDNA that are prevented from entry into the brain unless encapsulated in drug carriers. In many chronic disorders affecting the central nervous system, the BBB is physically intact which further limits the entry of large molecules. The desirable entry of such molecules will be made by formulation of particular drug carriers that will enable their transport into the brain endothelium, or even through the endothelium and into the brain. This review discusses the potential of different principles for drug therapy to the brain with these main emphases on drug transport through the BBB: i) the effects of molecular lipidization, ii) the involvement of solute nutrient carriers, iii) targeted delivery using small peptides with high membrane penetrating properties, iv) treatment with magnetic nanoparticles. These different principles for therapy are also discussed with focus on possibilities of their improvement for targeted delivery to the brain.

Development of a Novel Lipophilic, Magnetic Nanoparticle for in Vivo Drug Delivery

“…In addition, it could be speculated that the lipid bilayer provides an ability to fuse with the cell membrane increasing the efficiency by which the particle is endocytosed. Noteworthy, the MNPs do not lead to detectable toxicity of the cells [ 5 ].…”

“…They have been used for delivery of a plethora of drugs and especially delivery of anti-cancer drugs dominates [ 3 , 4 ]. A relatively new application of the MNPs is their use as a carrier for non-viral vectors intended for gene delivery and therapy, a process commonly referred to as magnetofection [ 5 ]. The concept of using MNPs for such purpose is generally identical to that of their application in targeted drug delivery, where an external or implanted magnet is used to attract the MNPs to the target site, which allows for targeted delivery of genetic material such as plasmid DNA.…”

“…This magnetic property can assist in targeting the MNPs to the site of interest and has been applied both in vitro and in vivo for several biomedical applications. The surface coating of the MNPs also attains a pivotal role in experimental assays, as it is important not only for their functionality but also for prevention of unwanted effects such as agglomeration, interaction with serum proteins or capture by the reticuloendothelial system (RES) leading to rapid clearing following systemic administration [ 3 , 4 , 5 ]. Hence, surface coating of the MNPs is crucial for both efficacy, but also safety, and therefore surface modification with biocompatible coatings are extensively studied.…”

A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment

“…A variety of active and specific transporter proteins are commonly expressed in the endothelial cells and involved in the transcellular transport systems, which mediate brain uptake and extrusion of various xenobiotic compounds including chemotherapeutic agents. To date, three main mechanisms of transcellular transport systems have been identified in the BBB (Figure 1(B)), which comprises receptor-mediated transport (RMT), carrier-mediated transport (CMT), and active efflux transport (AET) (Thomsen et al., 2012; Mikitsh & Chacko, 2014). RMT is one of the specific transcytosis mechanisms, which is based on endocytosis from the luminal side and exocytosis from the abluminal side of the endothelium (Lin, de Gooijer, et al., 2013).…”

Engineered nanomaterial uptake and tissue distribution: from cell to organism

“…60 Cationic particles or proteins bind nonspecifically to the negatively charged cell surface. [61][62][63] This triggers adsorptive CME. In contrast, the receptormediated process is highly selective and specific.…”